The development of vaccines for use as a treatment or prophylaxis against any one of a wide variety of different conditions is an extremely challenging scientific problem. In humans this is particularly challenging. However, because vaccines have been shown to be very successful at treating or preventing many types of conditions, there is an on-going need to identify new vaccine candidates, both to improve those vaccines currently on the market, but also to treat and protect against conditions for which no vaccine is currently available. One of the key tools required in the development of vaccines is a method of maintaining an on-going and authentic supply of the appropriate vaccine antigen formulation and also a model that can be used to understand immune responses, monitor disease progression or to test potential vaccine candidates. Preferably, such a method and model should exhibit both the complete patency and pathology of the condition following infection, and should also mimic the condition as closely as possible to that seen in a human host.
One particular disease for which there is a need to identify a vaccine candidate is the human hookworm infection, such as Necator americanus infection. It is currently estimated that a billion people worldwide harbour hookworm infections, making them a leading cause of anemia and malnutrition, particularly in children and women of child-bearing age in developing countries (Chan, M., et al., Parasitology 109:373–387 (1994); Hotez, P. J. and Pritchard, D. I., Scientific American 272(6):42–48 (1995); Stephenson, L., Pathophysiology of Intestinal Nematodes in The Geohelminths. Ascaris, Trichuris and Hookworm, C. V. Holland and M. W. Kennedy, Boston, Kluwer Academic Press, 2:39–61 (2001)). The infection is considered by many to represent a significant threat to the health and well being of afflicted communities and, consequently, efforts are being concentrated on developing a full understanding of the molecular biology of the host-pathogen interface, with a view to developing efficacious vaccines to protect against hookworm disease.
To this end, two major initiatives were recently announced, with the intention of increasing our knowledge of the molecular genetics of hookworms (The Wellcome Trust Beowulf Initiative) and to develop rationally designed vaccines for hookworm infection (The Hookworm Vaccine Initiative, Sabin Vaccine Institute and George Washington University). However, one of the major problems with these programs is that the hookworm lifecycle is difficult to maintain in animal models because of the subtle adaptation of the human hookworm to live in its definitive host. This also has the result that it is difficult to maintain an on-going supply of the hookworm larvae with the same molecular integrity as that which infects humans. As such, to support this work it is necessary to develop a method of maintaining a supply of human hookworms and also a vaccine model in animals that exhibits the full patency and pathology of human hookworm infection.
Several hookworm models are currently in existence, and these were developed to investigate the immunobiology of the human hookworm infection. These include the murine model of human hookworm infection, where an adult mouse is infected with the parasite. This model has several problems include the problem that the adult mouse is unable to retain adequate numbers of larvae in the gut. As a result, the model is unable to exhibit either the parasitology or the immunology of the human disease sufficiently accurately to be used as a mimic for the disease as exhibited in humans. The model cannot, therefore, be used for the development of either a vaccine or other medicaments.
In addition to the murine hookworm model, a canine model is also in use. Although this model is able to exhibit a form of the disease, the canine host is, unfortunately, unable to support human hookworm, and so the model utilises Ancylostoma caninum, the dog hookworm. While such a model is valuable for proof of principle studies, for example, with trial vaccines, it clearly has several limitations with respect to use as a model for studying human hookworm for the development of a human hookworm vaccine, because it utilizes a non-human hookworm species.
Finally, the hamster has been studied for use in work of this type. It has been shown that it is not possible to infect an adult hamster with anthropomorphic strains of the parasite which causes the disease, and, therefore, this species cannot be used as a model as such, whereby, for example, the animal is pre-vaccinated prior to challenge, etc. A further problem also exists in that the model does not respond to L3 larvae, again, because of the inability to use adult animals. However, the hamster has proved to be a valuable tool for the maintenance of a hookworm strain in the laboratory. The neonate is infected with the hookworm larvae; the hookworm is passaged through the animal, collected, and then either used for experimental purposes, or re-passaged to maintain further supplies. Hookworms obtained in this manner have proved useful for further understanding the protective inflammatory responses to hookworm challenge following vaccination (Ghosh, K. and Hotez, P., The Journal of Infectious Diseases 180:1674–1681 (1999); Hotez, P. J., et al., Immunological Reviews, 171:163–172 (1999); Liu, S., et al., Vaccine, 18:1096–1102 (2000); Culley, F. J., et al., European Journal of Immunology, 32(5):1376–1385 (2002)). However, recently it has been shown that hookworm passaged in this manner does not remain true to the authentic strain of human hookworm. Hence, there are several limitations when trying to utilise such material as part of a model for human hookworm, for example, for development of a vaccine, or other medicaments.
As such, to date, there are several problems associated with the known animal models for development of human hookworm vaccines, and it is, therefore, desirable to develop a well characterised primate model to enable the future vaccine development in a species closely allied to man (Homo sapiens). Such a model has several advantages, including that it is able to support the human hookworm infection throughout the whole life cycle, it provides an on-going source of authentic hookworm causative agent, it provides a more effective mimic for the immunological response of a human to the hookworm infection, and, therefore, provides a greater understanding of its pathology, and also provides a better vehicle for monitoring the efficacy of any vaccine candidates. The model and associated methods are used to provide materials required during the development program, test the efficacy and toxicity of desirable vaccine candidates, assess adjuvants, delivery routes and systems, frequency of inoculation, and to ascertain the immunological phenotype associated with protection with a higher degree of experimental validity than is available to date with known hookworm models.